Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.
Nature communications
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
10.1038/s41467-021-20918-w
Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence.
Tezze Caterina,Romanello Vanina,Desbats Maria Andrea,Fadini Gian Paolo,Albiero Mattia,Favaro Giulia,Ciciliot Stefano,Soriano Maria Eugenia,Morbidoni Valeria,Cerqua Cristina,Loefler Stefan,Kern Helmut,Franceschi Claudio,Salvioli Stefano,Conte Maria,Blaauw Bert,Zampieri Sandra,Salviati Leonardo,Scorrano Luca,Sandri Marco
Cell metabolism
Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging.
10.1016/j.cmet.2017.04.021
Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach.
Mendelson Michael M,Marioni Riccardo E,Joehanes Roby,Liu Chunyu,Hedman Åsa K,Aslibekyan Stella,Demerath Ellen W,Guan Weihua,Zhi Degui,Yao Chen,Huan Tianxiao,Willinger Christine,Chen Brian,Courchesne Paul,Multhaup Michael,Irvin Marguerite R,Cohain Ariella,Schadt Eric E,Grove Megan L,Bressler Jan,North Kari,Sundström Johan,Gustafsson Stefan,Shah Sonia,McRae Allan F,Harris Sarah E,Gibson Jude,Redmond Paul,Corley Janie,Murphy Lee,Starr John M,Kleinbrink Erica,Lipovich Leonard,Visscher Peter M,Wray Naomi R,Krauss Ronald M,Fallin Daniele,Feinberg Andrew,Absher Devin M,Fornage Myriam,Pankow James S,Lind Lars,Fox Caroline,Ingelsson Erik,Arnett Donna K,Boerwinkle Eric,Liang Liming,Levy Daniel,Deary Ian J
PLoS medicine
BACKGROUND:The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS AND FINDINGS:We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. CONCLUSIONS:We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.
10.1371/journal.pmed.1002215
In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
Ocampo Alejandro,Reddy Pradeep,Martinez-Redondo Paloma,Platero-Luengo Aida,Hatanaka Fumiyuki,Hishida Tomoaki,Li Mo,Lam David,Kurita Masakazu,Beyret Ergin,Araoka Toshikazu,Vazquez-Ferrer Eric,Donoso David,Roman Jose Luis,Xu Jinna,Rodriguez Esteban Concepcion,Nuñez Gabriel,Nuñez Delicado Estrella,Campistol Josep M,Guillen Isabel,Guillen Pedro,Izpisua Belmonte Juan Carlos
Cell
Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.
10.1016/j.cell.2016.11.052
Mitochondrial sirtuins, metabolism, and aging.
Journal of genetics and genomics = Yi chuan xue bao
Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Multiple signaling pathways that regulate metabolism also play critical roles in aging, such as PI3K/AKT, mTOR, AMPK, and sirtuins (SIRTs). Among them, sirtuins are known as a protein family with versatile functions, such as metabolic control, epigenetic modification and lifespan extension. Therefore, by understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.
10.1016/j.jgg.2021.11.005
Parkinson's disease is associated with DNA methylation levels in human blood and saliva.
Chuang Yu-Hsuan,Paul Kimberly C,Bronstein Jeff M,Bordelon Yvette,Horvath Steve,Ritz Beate
Genome medicine
BACKGROUND:Several articles suggest that DNA methylation levels in blood relate to Parkinson's disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers ("CpGs") and clusters of CpGs (co-methylation modules) in terms of biological pathways. METHODS:In a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA). RESULTS:Our cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10 and cg04772575 in ABCB9 p = 4.3 × 10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling. CONCLUSIONS:This study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.
10.1186/s13073-017-0466-5
DNA methylation in childhood asthma: an epigenome-wide meta-analysis.
Xu Cheng-Jian,Söderhäll Cilla,Bustamante Mariona,Baïz Nour,Gruzieva Olena,Gehring Ulrike,Mason Dan,Chatzi Leda,Basterrechea Mikel,Llop Sabrina,Torrent Maties,Forastiere Francesco,Fantini Maria Pia,Carlsen Karin C Lødrup,Haahtela Tari,Morin Andréanne,Kerkhof Marjan,Merid Simon Kebede,van Rijkom Bianca,Jankipersadsing Soesma A,Bonder Marc Jan,Ballereau Stephane,Vermeulen Cornelis J,Aguirre-Gamboa Raul,de Jongste Johan C,Smit Henriette A,Kumar Ashish,Pershagen Göran,Guerra Stefano,Garcia-Aymerich Judith,Greco Dario,Reinius Lovisa,McEachan Rosemary R C,Azad Raf,Hovland Vegard,Mowinckel Petter,Alenius Harri,Fyhrquist Nanna,Lemonnier Nathanaël,Pellet Johann,Auffray Charles, ,van der Vlies Pieter,van Diemen Cleo C,Li Yang,Wijmenga Cisca,Netea Mihai G,Moffatt Miriam F,Cookson William O C M,Anto Josep M,Bousquet Jean,Laatikainen Tiina,Laprise Catherine,Carlsen Kai-Håkon,Gori Davide,Porta Daniela,Iñiguez Carmen,Bilbao Jose Ramon,Kogevinas Manolis,Wright John,Brunekreef Bert,Kere Juha,Nawijn Martijn C,Annesi-Maesano Isabella,Sunyer Jordi,Melén Erik,Koppelman Gerard H
The Lancet. Respiratory medicine
BACKGROUND:DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS:We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS:27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects. INTERPRETATION:Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context. FUNDING:EU and the Seventh Framework Programme (the MeDALL project).
10.1016/S2213-2600(18)30052-3